Linking pathway gene expressions to the growth inhibition response from the National Cancer Institute's anticancer screen and drug mechanism of action

Molecular Target Class Is Predictive of In vitro Response Profile

“…The mean Pearson's distance for the pairwise comparison of these is 0.56 (± 0.11; n = 10). The specific mitotic targets of these compounds are largely unique, and their clustering is consistent with previous observations that the biological process targeted (mitosis in this case) can drive similarities in cellular response (15). The few cell lines whose proliferation is not affected by treatment with an antimitotic help define this compound cluster.…”

Pharmacogenomic Discovery Using Cell-Based Models

“…Application of this cell-based disease model to pharmacogenetics discovery has resulted in determination of transcription profiles predicting sensitivity to chemotherapeutics (Weinstein et al, 1997;Staunton et al, 2001;Blower et al, 2002;Huang et al, 2005a;Dai et al, 2006;Salter et al, 2008) as well as proteomic (Ma et al, 2006;Shankavaram et al, 2007;Stevens et al, 2008) and microRNA (Blower et al, 2008;Salter et al, 2008) profiles predicting drug response. Studies using these cells have successfully identified polymorphisms in candidate genes associated with drug response in vitro (Le Morvan et al, 2006;Jarjanazi et al, 2008;Puyo et al, 2008;Sasaki et al, 2008).…”

Targeting changes in cancer: assessing pathway stability by comparing pathway gene expression coherence levels in tumor and normal tissues

“…The pathways that contain known cancer genes have been examined in particular, and their behavior compared with that of other pathways. Finally, we have applied our previously developed methods that connect pathways to small molecules that putatively disrupt their function (41) in an attempt to propose agents that might selectively target cancer-relevant pathways.…”

“…We have organized the tissue gene expression patterns in terms of the widely used, publicly available gene annotations (pathways or functional categories) defined by Kyoto Encyclopedia of Genes and Genomes (KEGG), BioCarta, and Gene Ontology (GO). The gene expression coherence levels in these pathways have been evaluated using our previously developed methods (41) and compared between tumor and normal samples. Pathways that show a significant change in their cohesiveness, which may be an indication of instability in their gene regulation, are identified.…”

“…Various computational methods have been proposed to analyze gene expression patterns within predefined pathways (37 -39). We have previously presented strategies to evaluate the level of coexpression in pathways or functionally related groups of genes using gene expression patterns measured in the National Cancer Institute's 60-cell tumor screen (40) and related pathway gene expressions to differential cytotoxicity of potential anticancer agents screened in the same cell lines and their mechanisms of action (41). The purpose of this study is to extend our analysis to include gene expression data obtained from human tumor and normal tissue samples and evaluate these observations for the purpose of assessing which pathways are deregulated in cancer, and to apply these results toward the development of a rationale for selecting pathway-specific chemo-interventions.…”